Reduction of serum cholesterol levels with the dimethyl acetal of 1-(2,4-di-sec-butylphenoxy)-2-propanone

ABSTRACT

Pharmaceutical compositions containing the dimethyl acetal of 1(2,4-di-sec-butylphenoxy)-2--propanone and methods of producing a hypocholesteremic effect in mammals are provided.

United States Patent [191 Barnhart et al.

[ June 28, 1974 [73] Assignee: The Dow Chemical Company,

I Midland, Mich. [22] Filed: Mar. 5, 1973 [2]] Appl. No.: 337,863

[52] US. Cl. 424/341, 260/613 D [51] Int. Cl A61k 27/00 [58] Field ofSearch 424/340, 341; 260/613 D [56] References Cited UNITED STATESPATENTS 3,409,661 l 1/1968 Schultz et al. 424/317 X Primary Examiner--Albert T. Meyers Assistant Examiner-Frederick E. Waddell Attorney,Agent, or Firm-Gary D, Street 5 ABSTRACT Pharmaceutical compositionscontaining the dimethyl acetal of.1-(2,4-di-sec-butylphenoxy)-2--pr0pan0ne and methods of producing ahypocholesteremic effect in mammals are provided.

4 Claims, N0 Drawings 1 REDUCTION OF SERUM CHOLESTEROL LEVELS WITH THEDIMETHYL ACETAL OF 1 2,4-DI-SEC-BUTYLPHENOXY )-2 -PROPANONE SUMMARY OFTHE INVENTION DETAlLED DESCRIPTION According to the present invention,there are provided pharmaceutical compositions containing as the activeingredient the compound of the formula:

OH; OCH: I CHsCHzH OCHaCHa 'GHi I H-CHr-CHa in the presence of anon-toxic pharmaceuticallyacceptable inert diluent or carrier therefor.The active dimethyl acetal of l-(2,4-di-sec-butylphenoxy)-2- propanonecompound of the present invention (hereinafter referred to as thepropanone compound") is a liquid which is of low solubility in water andis somewhat soluble in many organicsolvents useful as pharmaceuticalcarriers.

It has been found that the propanone compound employed in accordancewith the invention, when administered internally, i.e.,' enterally orparenterally, to mammals in a hypocholesteremic amount has the effect oflowering the blood cholesterol content, that is, the amount ofcholesterol in the blood serum of the animal. The propanone compound hasparticularly been found to bring about a substantial lowering of serumcholesterol .when administered orally to animals in the form oforally-ingestible compositions. The administration of ahypocholesteremic amount of the propanone compound to an animal iscritical and essential to the prac tice of the method of the invention.A hypocholes teremic amount of the propanone compound is that amountwhich effectuates a substantial reduction of serum cholesterol levels inthe animal administered the compound. Whether or not sufficient of thepropanone compound is administered under particular circumstances can beascertained by the conventional procedure of measuring serum cholesterollevels of animals administered the propanone compound and comparing theresults with the cholesterol levels observed in similar untreatedanimals. Whether-or not a reduction is regarded as substantial dependson a variety of factors such as the result desired, the species ofanimal and variations in cholesterol levels occurring when no com poundis administered.

The hypocholesteremic amount of the propanone compound to beadministered to an animal, that is, the amount which is effective tosubstantially lower the serum cholesterol level, can vary depending uponsuch factors as the size, weight and age of the animal treated, thedesired serum cholesterol level to be obtained, whether or not theanimal is hypercholesteremic (e.g.,

whether or not the original cholesterol level is above normal), theperiod of administration and the method of administrationaThe propanonecompound can be administered in a hypocholesteremic amount of from aboutl milligram to about 1 gram per kilogram. It can be administered orallyin single doses or repeated multiple doses; if desired, injectablecompositions comprising the propanone compound may be utilized forintraperitoneal injection. In general, the propanone compound isadministered in daily oral dosages of from about 1 to about 5 milligramsto about 1,000 milligrams of the active compound per kilogram of bodyweight of the animal to be treated.

The propanone compound is preferably administered as a composition indosage unit form. Such compositions can be prepared by known techniquesand preferably contain from about 1 to about 1,000 milligrams of theactive compound. The compound can also be administered in compositionsadapted to be fed as part or all of the animal diet.

In forming the compositions of the invention, the active propanonecompound is incorporated in a nontoxic pharmaceutical carrier. In thepresent specification and claims, the term non-toxic carrier" refers toconventional excipients and includes nutritive compo sitions such as asolid or liquid foodstuff. ln-the present specification and claims, theterm foodstuff refers to non-toxic carriers which are not only non-toxicand non-sensitizing, but which are also digestible and otherwiseutilizable in the animal metabolism. In the present specification andclaims, the term excipient refers to known pharmaceutical excipientswhich are substantially non-toxic, non-sensitizing and withoutsignificant pharmacological activity when compositions of the inventionare administered at. dosages consistent with good hypocholesteremicactivity. Certain non-toxic carriers such as starch are both foodstuffsand pharmaceutical excipients. In the composition of the invention, thenon-toxic carrier employed cooperates with the active ingredient toprepare a desirable composition for administration and to release anddisperse a hypocholesteremic amount of the active ingredient within theanimal body after administration. Particular non-toxic carriers can beselected by conventional procedures to prepare compositions which canvary somewhat in physical form, oral acceptance by animals(palatability), onset and duration of hypocholesteremic activity and thelike.

The identity of the pharmaceutical carriers which are used informulating the propanone compound into dosage fonns which are suitablefor enteral or parenteral administration will be immediately apparent tothose skilled in the art. Suitable pharmaceutical carriers are describedin Remingtons Pharmaceutical Sciences (14th Ed.) by E. W. Martin, awell-known reference text in this field. A preferred pharmaceuticalcarrier is a surface-active dispersing agent. Preferred compositions arethose in which the non-toxic carrier is selected from the groupconsisting of inert solid diluents, suspending agents and surface-activedispersing agents. Particularly preferred are the above compositionswherein the non-toxic carrier further comprises a solid or liquidfoodstuff which can include a water-soluble vitamin.

The term finely divided inert solid pharmaceutical excipient" refers tosolid, non-toxic, physiologically inert or undigestible pharmaceuticalcarriers having a particle size small enough to pass a screen having 12meshes to the inch. Representative finely divided inert solids which canbe employed include silica gel or silica, chalk, magnesium carbonate,magnesium stearate, talc, calciumsulfate, cellulose, micro-crystallinecellulose and the like. In such compositions, the excipient cooperateswith the active ingredient to facilitate the action thereof and dispersethe same internally of the animal organism upon oral administration ofthe composition. Such compositions can also be employed as concentratesfor admixture with and dispersal of the active ingredient throughout theultimate composition.

Acceptable formulations for oral use can be prepared in the usual mannerto provide an aqueous suspension, an elixir or a solid dosage unit form(e.g., tablet, powder or capsule), for example, two-piece hard gelatincapsules may be filled with a'mixture of the active ingredient andexcipients (e.g., starch, talc, stearic acid, and/or magnesiumstearate). Also, one piece gelatin capsules containing the same amountof medicament may be prepared using sufficient corn oil or othersuitable vegetable oil, to render the compound capsulatable. Tablets maybe prepared by using starch, lactose or other conventional excipients,and may be scored to enable the administration of fractional dosages, ifdesired. Any of the tableting material used in pharmaceutical practicemay be employed. Liquid preparations may be in the form of suspensions,emulsions, syrups or elixirs of the active substance in water or otherliquid medium commonly used for making orally acceptable pharmaceuticalformulations, such as liquid paraffin, or a syrup elixir base. Suchformulations can contain from about 0.02 to about 95 or more weightpercent, usually .from about 0.1 to about 50 weight percent, of activeingredient based on the total weight of the dosage form, there beingenough active ingredient to provide an amount within the dosage levelsstated above.

The active substance may also be made up in a form suitable forparenteral administration, i.e., as a suspension in sterile water or anorganic liquid usually employed for injectable preparations, for examplea vegetable oil such as olive oil, or a sterile solution in an organicsolvent Such formulations can contain from about 0.02 to about 95 ormore weight percent, usually from about 0.1 to about 25 weight percent,of active ingredient based on the total weight of the dosage form, therebeing enough active ingredient to provide an amount within the dosagelevels stated above.

The active ingredient can also be incorporated in a nutritive foodstuffsuch as, for example, butter, margarine, edible oils, carbohydrates andthe like. Such nutritive compositions are adapted to be administered asapartial or total diet or as a supplement to the diet. Such compositionspreferably contain from about 0.02 or less to about 2.0 or more percentof the active ingredient when administered as the total diet. Thecompositions can contain higher concentrations of the active ingredientwhen administered as a supplement.

Moreover, preservatives, stabilizers, wetting agents, buffers, and thelike can be incorporated, if desired, into the above formulations.Additionally, the formulations may also contain other therapeuticallyvaluable substances such as other complementary hypolipidemic,hypocholesteremic or hypoglycerin agents as well as vitamins,analgesics, androgens, and the like compatible with the present compoundcan be included in the present formulations to secure advantageouscombination therapy.

The term unit dosage form as used in the specification and claims hereinrefers to physically discrete units suitable as unitary dosages, eachunit containing a predetermined quantity of active material calculatedto produce the desired therapeutic effect in association with therequired pharmaceutical diluent, carrier or vehicle. The specificationfor the novel unit dosage forms of this invention are dictated by anddirectly dependent on (a) the unique characteristics of the activematerial and the particular therapeutic effect to be achieved and (b)the limitations inherent in the art of compounding such an activematerial for therapeutic use, as disclosed in detail in thisspecification, these being features of the present invention. Examplesof suitable unit dosage forms are tablets, capsules, pills, powderpackets, wafers, cachets, granules, solutions or suspensions for oral orsterile injectable use, suppositories, and segregated multiples of anyof the foregoing, and other forms alluded to herein.

The propanone compound of the present invention can also be formulatedas a concentrate composition which is adapted to be diluted by admixturewith liquid or solid foodstuffs. Such concentrated compositions arepreferably prepared by mixing the active propanone compound with afinely divided inert solid carrier such as silica gel, talc, chalk orthe like or a finely divided foodstuff such as casein, sugar or thelike, or mixtures thereof. The concentrated compositions can alsoinclude additional ingredients such as water-soluble vitamins,fat-soluble vitamins, proteins, amino acids, carbohydrates and the like.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The following examplesillustrate the present invention but are not to be construed aslimiting.

Example 1 One part of the dimethyl acetal ofl-(2,4-di-secbutylphenoxy)-2-propanone compound is mixed with threeparts of silica gel and the resulting mixture is dried to obtain aconcentrated composition containing 25 percent of the active propanonecompound. A portion of the concentrate composition is employed toprepare a nutritive composition by intimately mixing 0.5 part of theconcentrated composition with 99.5 parts of standard animal feed on aconventional roller mill. There is thus obtained a nutritive compositionsuitable for oral administration to animals for the purpose of loweringserum cholesterol levels. The composition is adapted to be fed as theentire animal diet.

Example 2 In substantially the same procedure as described above inExample 1, separate portions of balanced rodent mash and a concentratecomposition are mixed together to prepare a composition containing 0.12percent by weight of the dimethyl acetal ofl-(2,4-di-secbutylphenoxy)-2-propanone compound. Separate groups of malemice of the same origin and past history were fed for two weeks onseparate diets consisting of the above-described composition. A separategroup of check mice was similarly fed for two weeks on a similar dietwhich contained none of the propanone compound to serve as a check. Atthe end of the two week period,

the mice were exsanguinated under anesthesia. Serum cholesterol wasdetermined by taking a -0.05 milliliter aliquot of serum from each mouseand adding the aliquot to 3 milliliters of a 0.08 percent solution offerric chloride in pure acetic acid. The serum was mixed with the ferricchloride-acetic acid solution and allowed to stand for to minutes toflocculate protein. The protein was precipitated by centrifugation andthe clear supernatant was transferred to a stoppered test tube. Twomilliliters of sulfuric acid were added to the supernatant and mixedwell. The tubes were then left to stand exposed to air for to 30minutes. Serum cholesterol was determined by measuring percenttransmission at a wave length of 560 millimicronsin a spectrophotometerand comparing the percent transmission to that observed with solutionscontaining known amounts of cholesterol. The serum cholesterol levelfound in the check group of mice was used as the basis for calculatingpercentage reduction of cholesterol. A 37 percent reduction in the serumcholesterol level was obtained with the dimethyl acetal ofl-(2,4-di-secbutylphenoxy)-2-propanone compound employed at the dosagerate of 0.12 percent of the diet.

Example 3 Fifty parts of one of the dimethyl acetal of1-(2,4-disec-butylphenoxy)-2-propanone compound is inti-.

Example 4 A mixture consisting of 250 parts of dimethyl acetal ofl-(2,4-di-sec-butylphenoxy)-2-propanone compound and 8 parts of wheatstarch and 6 parts of gelatin in 75 parts of water was prepared,granulated, passed through an 8 mesh screen and dried. The granulate isthen passed througha 12 mesh screen and mixed well with 13 parts of talcand 4 parts of magnesium stearate. The resulting mixture is compressedinto tablets weighing 6 grams each. The tablets are scored by knownmethods and are adapted to be administered orally as a single dosage oras multiple dosages, each comprising one-half or one-fourth of a singletablet.

Example 5 An injectable solution manufactured in the usual mannercomprises the following composition:

Water added, I ml.

The dimethyl acetal of l-(2,4-di-sec-butylphenoxy)- 2-propanone compoundemployed in the compositions and method of the present inventionisprepared by adding 2,4 di-sec-butylphenyl-2-propynyl ether (46 grams;0.24 mole) in 50 milliliters (ml.) of methanol to a borontrifluorideetherate (3 mls.), and methanol (150 ml.) mixture containing lgram ofred mecuric oxide and 1 crystal of trichloroacetic acid at a temperatureof about 50 C. The 2,4-di-sec-butylphenyl-2 propynyl ether was addeddropwise, with agitation of the mixture, to the mixture over a period ofabout minutes. The resulting reaction mixture was then heated-at atemperature of from about 6065 C. for a period of about 4 hours and thenallowed to stand at ambient temperatures for a period of about 16 hours.A small amount of Na CO was added to the mixture and the mixturefiltered and subsequently distilled. As a result of these operations,the desired dimethyl acetal of l-(2,4 di-sec-butylphenoxy)-2-propanonecompound was obtained as an amber oily liquid having a refractive index(n of 1.4890.

We claim:

1. A pharmaceutical composition comprising a hypocholesteremic amount ofthe dimethyl acetal of l-(2,4- di-sec-butylphenoxy)-2-propanone incombination with a pharmaceutical carrier.

2. A method of treating hypercholesteremia in the blood of a mammalcomprising administering internally to said mammal an effective amountof the dimethyl acetal of l-(2,4-di-sec-butylphenoxy)-2-propanone incombination with a pharmaceutical carrier.

3. The method of claim 2 which comprises administering a daily dosage offrom about 1 to about 1,000 mg/kg.

4. The method of claim 2 wherein the dimethyl acetal of l-(2,4-di-sec-butylphenoxy )--2-propanone com pound is administered orally.

2. A method of treating hypercholesteremia in the blood of a mammalcomprising administering internally to said mammal an effective amountof the dimethyl acetal of 1-(2,4-di-sec-butylphenoxy)-2-propanone incombination with a pharmaceutical carrier.
 3. The method of claim 2which comprises administering a daily dosage of from about 1 to about1,000 mg/kg.
 4. The method of claim 2 wherein the dimethyl acetal of1-(2,4-di-sec-butylphenoxy)-2-propanone compound is administered orally.